Structural defects in cilia of the choroid plexus, subfornical organ and ventricular ependyma are associated with ventriculomegaly

Abstract

BackgroundHydrocephalus is a heterogeneous disorder with multiple etiologies that are not yet fully understood. Animal models have implicated dysfunctional cilia of the ependyma and choroid plexus in the development of the disorder. In this report, we sought to determine the origin of the ventriculomegaly in four Bardet Biedl syndrome (BBS) mutant mouse strains as models of a ciliopathy.MethodsEvans Blue dye was injected into the lateral ventricle of wild- type and BBS mutant mice to determine whether obstruction of intra- or extra-ventricular CSF flow contributed to ventriculomegaly. Transmission electron microscopy (TEM) was used to examine the ultrastructure of the choroid plexus, subfornical organ (SFO), subcommisural organ (SCO), and ventricular ependyma to evaluate their ultrastructure and the morphology of their primary and motile cilia.Results and discussionNo obstruction of intra- or extra-ventricular CSF flow was observed, implying a communicating form of hydrocephalus in BBS mutant mice. TEM analyses of the mutants showed no evidence of choroidal papillomas or breakdown of the blood:CSF barrier. In contrast, structural defects were observed in a subpopulation of cilia lining the choroid plexus, SFO, and ventricular ependyma. These included disruptions of the microtubular structure of the axoneme and the presence of electron-dense vesicular-like material along the ciliary shaft and at the tips of cilia.ConclusionsAbnormalities in cilia structure and function have the potential to influence ciliary intraflagellar transport (IFT), cilia maintenance, protein trafficking, and regulation of CSF production. Ciliary structural defects are the only consistent pathological features associated with CSF-related structures in BBS mutant mice. These defects are observed from an early age, and may contribute to the underlying pathophysiology of ventriculomegaly.

Ciliopathy Is Differentially Distributed in the Brain of a Bardet-Biedl Syndrome Mouse Model

“…Consistent with the findings of Swiderski and colleagues [6] we observed that deletion of the Bbs4 gene produced enlarged ventricles and reduced mass of the hippocampus and striatum compared to WT littermates.…”

“…Comparison of the general morphology of the brains of WT and Bbs4 -/- mice confirmed the gross differences in central nervous system structure (CNS) documented previously for the Bbs1 knock-in model [23] and Bbs deletion mutants [6]. Consistent with the findings of Swiderski and colleagues [6] we observed that deletion of the Bbs4 gene produced enlarged ventricles and reduced mass of the hippocampus and striatum compared to WT littermates.…”

BBS4 is required for IFT coordination and basal body number in mammalian olfactory cilia.

“…These observations support the idea that basal body reduction is not concomitant to cilia loss. However, because cilia and basal bodies appeared structurally intact in hippocampal and amygdala neurons, as well as multiciliated cells in Bbs4 −/− mutant mice (Agassandian et al, 2014;Shah et al, 2008;Swiderski et al, 2012), the impact of BBS4 loss on OSNs basal bodies could be unique to these neurons. It is possible that OSNs utilize alternative mechanisms for basal body biogenesis and maintenance that makes the neurons sensitive to loss in the absence of BBS4.…”

A novel hypomorphic allele ofSpag17causes primary ciliary dyskinesia phenotypes in mice

“…The Aqueduct of Sylvius in the Pcdo mutants appeared stenotic with collapsed walls and was associated with a slight enlargement of the SCO (Figure 4). In other models, patency of the aqueduct is compromised in the presence of dysfunctional SCO or SCO ependymal cilia (Pérez-Fígares, Jimenez et al 2001, Swiderski, Agassandian et al 2012, leading to aqueductal stenosis or occlusion and non-communicating hydrocephalus. Ciliary beating function and directionality of the beating were defective when assayed in intact aqueduct lumen.…”